rs142604406

Variant names:

• chr16-19466155-C-A
• rs142604406
• NM_001261841.2:c.1559C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-19466155-C-A
• chr16-19466155-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001261841.2(TMC5):​c.1559C>A​(p.Ala520Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A520V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900
• Publications: 2 publications found

Genes affected

TMC5 (HGNC:22999): (transmembrane channel like 5) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000260592 (HGNC:58394):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052850127).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261841.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC5	NM_001261841.2	MANE Select	c.1559C>A	p.Ala520Glu	missense	Exon 9 of 22	NP_001248770.1	Q6UXY8-1
	TMC5	NM_001105248.1		c.1559C>A	p.Ala520Glu	missense	Exon 9 of 22	NP_001098718.1	Q6UXY8-1
	TMC5	NM_001308161.1		c.1559C>A	p.Ala520Glu	missense	Exon 9 of 21	NP_001295090.1	Q6UXY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC5	ENST00000542583.7	TSL:2 MANE Select	c.1559C>A	p.Ala520Glu	missense	Exon 9 of 22	ENSP00000446274.2	Q6UXY8-1
	TMC5	ENST00000381414.8	TSL:1	c.1559C>A	p.Ala520Glu	missense	Exon 9 of 21	ENSP00000370822.4	Q6UXY8-2
	TMC5	ENST00000219821.9	TSL:1	c.821C>A	p.Ala274Glu	missense	Exon 5 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000994 AC: 25 AN: 251460 AF XY: 0.000118

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000325 AC XY: 236 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000432 AC: 480 AN: 1112006

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.9
DANN	Benign	0.73
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.090
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.081
Sift	Benign	0.20	T
Sift4G	Benign	0.083	T
Polyphen		0.83	P
Vest4		0.38
MVP		0.35
MPC		0.48
ClinPred		0.081	T
GERP RS		-0.56
Varity_R		0.11
gMVP		0.73
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142604406; hg19: chr16-19477477;